Novel Antimicrobial Host Defense Peptides: Design and Immunomodulatory Function

新型抗菌宿主防御肽：设计和免疫调节功能

• 批准号: RGPIN-2022-03089
• 负责人: Straus, Suzana
• 金额: $ 2.11万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748112
• 关键词: Novel; Antimicrobial; Host; Defense; Peptides

Antimicrobial resistance (AMR) is an increasingly important global health concern, with simple bacterial infections becoming once again prevalent and lethal. The recent SARS-CoV2 pandemic has further exacerbated resistance, because antibiotics are being heavily overprescribed to COVID-19 patients even when only small proportions display bacterial co-infection. Host defense peptides (HDPs) are a viable solution against resistant bacteria due to their diverse mechanisms of action, such as direct bacterial killing as well as immunomodulatory properties. Despite their promise, HDPs are however seldom used in a clinical setting because their therapeutic efficacy is limited by rapid degradation, systemic toxicity, and low bioavailability. In the last 6 years, the Straus group has done extensive work to improve the applicability of HDPs. New peptides, which are highly active against resistant bacteria, were generated and their mechanism of action was elucidated. Moreover, formulation and conjugation strategies that mitigate the limitations of HDPs were developed. The resulting approaches show tremendous promise. However, in order to further broaden the usage of HDPs, three important areas require further in-depth study: 1) understanding how immunomodulatory HDPs (iHDPs) function at a molecular level; 2) tailoring delivery strategies for iHDPs by understanding how conjugation impacts the mechanism of action; and 3) developing approaches to repurpose commonly used antibiotics in order to have ready solutions to the AMR problem. Specifically, this proposal outlines objectives that will enable a team of diverse HQP to develop as independent researchers, with strong training in interdisciplinary, collaborative research and thorough knowledge of biophysical techniques (e.g. NMR, ITC, CD, etc.). Trainees will benefit from a work environment where equity, diversity and inclusion are core values: most trainees in the Straus group are women and from visible minorities. To understand the mechanism of action of iHDPs (aim 1), two PhD students will determine how these peptides affect macrophage differentiation by studying HDP/macrophage interactions, a new area of research. They will also investigate how amino acid composition modulates immunomodulatory activity. In terms of conjugation (2), two PhD students will further fine-tune current approaches and adapt them to iHDPs, as well as determine (e.g. using whole bacterial cell NMR) how the mode of action of the polymer-HDP conjugate differs from the HDP alone. Finally, using our knowledge on conjugation, a PhD student will devise methods to create new antibiotics (3) consisting of commonly used molecules plus HDPs. In this way, the benefit of current antibiotics (high activity, low toxicity) can be harnessed, while minimizing resistance effects. Overall, the proposed program will ensure that novel fundamental knowledge required to address the AMR problem is obtained, so that tangible solutions can be developed.

抗生素耐药性（AMR）是一个日益重要的全球健康问题，简单的细菌感染再次变得普遍和致命。最近的SARS-CoV 2大流行进一步加剧了耐药性，因为抗生素被严重过量地用于COVID-19患者，即使只有一小部分患者显示细菌合并感染。宿主防御肽（HDPs）是抵抗耐药细菌的可行解决方案，这是由于其不同的作用机制，例如直接细菌杀伤以及免疫调节特性。尽管它们有希望，但由于它们的治疗功效受到快速降解、全身毒性和低生物利用度的限制，因此在临床环境中很少使用HDPs。 在过去的6年里，Straus小组做了大量工作来提高HDPs的适用性。产生了对耐药细菌具有高活性的新肽，并阐明了其作用机制。此外，开发了减轻HDPs限制的制剂和缀合策略。由此产生的方法显示出巨大的前景。然而，为了进一步扩大HDP的使用，需要进一步深入研究三个重要领域：1）了解免疫调节HDP（iHDP）如何在分子水平上发挥作用; 2）通过了解结合如何影响作用机制来定制iHDP的递送策略; 3）开发重新使用常用抗生素的方法，以便随时解决AMR问题。具体而言，该提案概述了目标，使不同的HQP团队能够发展为独立的研究人员，在跨学科，合作研究和生物物理技术（例如NMR，ITC，CD等）的全面知识方面进行了强有力的培训。学员将受益于一个以公平、多样性和包容性为核心价值观的工作环境：斯特劳斯集团的大多数学员是妇女和明显的少数群体。为了了解iHDP的作用机制（目的1），两名博士生将通过研究HDP/巨噬细胞相互作用（一个新的研究领域）来确定这些肽如何影响巨噬细胞分化。他们还将研究氨基酸组成如何调节免疫调节活性。在缀合方面（2），两名博士生将进一步微调当前的方法，使其适应iHDP，并确定（例如使用全细菌细胞NMR）聚合物-HDP缀合物的作用模式与单独的HDP有何不同。最后，利用我们在结合方面的知识，一名博士生将设计出由常用分子和HDPs组成的新抗生素的方法。通过这种方式，可以利用当前抗生素的益处（高活性，低毒性），同时最大限度地减少耐药性影响。总的来说，拟议的计划将确保获得解决AMR问题所需的新的基础知识，以便开发切实可行的解决方案。